Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as weight loss, reductions in hyperlipidemia and hypertension constitute the only preventive strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Recent work by us and others has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages suggesting that attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy-lysosomal biogenesis, shows that enhancing its function in macrophages leads to reductions in atherosclerosis. A critical TFEB target is the autophagy chaperone p62/SQSTM1 which mediates the removal of cytotoxic protein aggregates. Our work has shown that clearance of the p62-enriched cargo in macrophages is a novel therapeutic strategy. In specific aim 1, we will determine the predominant p62-dependent autophagic processes in macrophages that underlie TFEB- mediated atheroprotection. In specific aim 2, we explore the potential atheroprotective benefits of HSP104, a novel disaggregase system mostly studied in simple organisms. This approach will be complementary to the autophagy studies since it is a completely autophagy-independent mechanism of clearing macrophage protein aggregates. Overall, this proposal will test the hypothesis that harnessing the macrophage degradative response to clear protein aggregates can be a novel approach to treat atherosclerosis.